Abstract PO4-05-07: Differential dynamics of fragmentomic and epigenetic circulating tumor DNA (ctDNA) features in first-line Palbociclib and Ribociclib treatment for Hormone Receptor (HR) positive, HER2 negative metastatic breast cancer (MBC)

Abstract Background: Cyclin-dependent kinase inhibitors (CDK4/6i) in combination with endocrine therapy (ET) represent the cornerstone for the management of HR positive, HER2 negative MBC. However, the lack of prospective cohorts comparing the distinctions among palbociclib (PAL), ribociclib (RIB) and abemaciclib (ABE) poses a significant clinical knowledge gap. The aim of this ancillary analysis was to explore the differential clinical impact of CDK4/6i by leveraging new ctDNA biomarkers in a prospective clinical study. Methods: A total of 114 patients (pts) with HR positive, HER2 negative MBC were prospectively enrolled in the multicenter MAGNETIC.1 study (CRO-2018-56) from January 2018 to January 2023. At baseline (BL) and every 3 months (mos.), ctDNA samples were collected concurrently with radiological restaging. The samples were then analyzed through methylation-specific (MS) droplet digital PCR (ddPCR), ddPCR fragmentomics, and next generation sequencing. Matched pairs of variations were tested through Wilcoxon signed rank test, and survival was analyzed by log-rank test. Results: Out of the 114 pts enrolled, 59 received PAL, 48 RIB, and 16 ABE. In the de novo subgroup, 51.4 % of pts were treated with PAL, 42.9% with RIB, and 5.7% with ABE. Among the pts who received PAL, 7 harbored an ESR1 mutation at BL (D538G: 2, H377R: 1, Y537N: 1, Y537S: 3). Additionally,12 pts had PIK3CA mutations, and 2 pts had AKT1 mutations. In the RIB group, 5 and 2 pts, respectively, had a PIK3CA- and AKT-mutated MBC, while no ESR1 mutations were detected. When comparing matched pairs of variations, it was found that at BL, at first radiological restaging (T1), and at 6 mos. after initiation of CDK4/6i (T2), only PAL showed significantly higher levels of promoter A and B methylation (promA and promB) at T1 (P = 0.0005 and P = 0.0056, respectively for promA and promB), A significant decrease in promA and promB levels was detected at T2 for PAL (P = 0.0005 and P < 0.0001 respectively for promA and promB) but not for RIB. Both PAL and RIB demonstrated a significant decrease in ctDNA short fragments at T1 (P = 0.0263 for PAL and P = 0.0001 for RIB), However, PAL showed a significant rebound at T2, with an increase in 80% of samples (P = 0.0014). The same was not seen with RIB. After a median follow-up of 34.8 mos., there were no significant differences between PAL and RIB in terms of PFS (P= 0.2573) and OS (P= 0.3783). The PFS rates at 12 and 24 mos. were 69% and 48% for PAL, and 76% and 64% for RIB. The OS rates at 12 and 24 mos. were 94% and 84% for PAL, compared to 97% and 82% of RIB, respectively. Conclusions This analysis of MAGNETIC.1 highlighted significant differences in ctDNA biomarkers between palbociclib and ribociclib, suggesting their potential impact on the development of endocrine resistance. Further biomarker-driven clinical trials leveraging this concept are needed to refine the sequencing algorithms for CDK4/6i. Citation Format: Claudia Noto, Linda Cucciniello, Elisabetta Molteni, Silvia Bolzonello, Alessandra Franzoni, Lucia Da Ros, Silvia Buriolla, Arianna Dri, Lorenzo Foffano, Simon Spazzapan, Stefania Russo, Brenno Pastò, Giulia Cudia, Giada Targato, Serena Della Rossa, Marta Bonotto, Alessandro Marco Minisini, Giuseppe Damante, Barbara Belletti, Lorenzo Gerratana, Fabio Puglisi. Differential dynamics of fragmentomic and epigenetic circulating tumor DNA (ctDNA) features in first-line Palbociclib and Ribociclib treatment for Hormone Receptor (HR) positive, HER2 negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-07.